KR102465692B1 - High refractive index hydrophilic material - Google Patents

Abstract

(a) a first monomer subunit comprising (i) a polymerized (meth)acrylate group and an aliphatic carbon moiety comprising at least two hydroxyl substituents or (ii) a polymerized (meth)acrylamide group, ( b) a polymerized (meth)acrylate group, (i) an aryloxy moiety comprising at least one halogen and (ii) an aliphatic carbon moiety connecting the aryloxy moiety with the polymerized (meth)acrylate group. a second monomer subunit different from the first monomer subunit, wherein the aliphatic carbon moiety optionally comprises at least one hydroxyl substituent, (c) polymerized (meth)acryl A hydrophilic intraocular lens with a high refractive index, comprising at least one copolymer comprising a third monomer subunit, different from the first and second monomer subunits, comprising a late group and at least one alkoxyalkoxyalkyl side group ( IOLs).

Description

High refractive index hydrophilic material

related application

This application claims priority to U.S. Provisional Application Serial No. 62/435,441 and U.S. Application Serial No. 15/586,890, filed on December 16, 2016, the complete disclosures of which are incorporated herein by reference in their entirety.

Several types of intraocular lenses (IOLs) are known. For example, one-piece intraocular lenses and composite intraocular lenses having multiple parts are known. In an integral intraocular lens, both the optical and non-optical parts are made from one material. The non-optical portion of the IOL is referred to as the haptic portion and is used for attachment purposes.

Foldable hydrophobic and hydrophilic IOLs have been described in the prior art, for example, in US Pat. Nos. 7,947,796, 7,387,642, 7,067,602, 6,517,750 and 6,267,784, each of which is incorporated herein by reference in its entirety. Also, see, for example, US Patent Publication Nos. 2013/0253159, 2008/0221235, 2006/0276606, 2006/0199929, 2005/0131183, 2002/0058724, 2002/0058723 and 2002/0027301 WO/21195 together with Each is incorporated herein by reference in its entirety).

Additionally, lens materials comprising the monomer 2-hydroxy-3-phenoxypropyl acrylate are in the prior art, for example WO 2010/128266, WO 2001/018079, WO 2000/079312, WO 96/40303 and US Patent No. 5,693,095. Lens materials 2-Ethoxyethyl methacrylate is also known in the art as a compound with a low glass transition temperature. See, eg, Garcia, F., et al., J. of Polymer Science: Part A: Polymer Chemistry, Vol. 40, 3987-4001 (2002).

However, it has a high refractive index, has no adhesive properties after implantation of the IOL, and has a combination of difficult-to-achieve properties such as hydrophilicity, which can provide small incision implantability while maintaining good mechanical properties and facilitating better surgical outcomes. A need exists for improved IOL materials comprising materials.

Embodiments described herein include, for example, copolymers, lenses, intraocular lenses, blanks for intraocular lenses, compositions, and methods of making and using intraocular lenses.

Some embodiments provide a hydrophilic intraocular lens comprising at least one copolymer comprising, for example: (a) (i) polymerized (meth)acrylate groups, and at least two hydroxyl substituents; an aliphatic carbon moiety comprising or (ii) a first monomer subunit comprising a polymerized (meth)acrylamide group, (b) a polymerized (meth)acrylate group, (i) an aryloxy group comprising at least one halogen. and (ii) at least one side group comprising an aliphatic carbon moiety linking the aryloxy moiety with the polymerized (meth)acrylate group, wherein the aliphatic carbon moiety optionally carries at least one hydroxyl substituent a second monomer subunit different from the first monomer subunit, comprising: (c) first and second monomer subunits comprising a polymerized (meth)acrylate group and at least one alkoxyalkoxyalkyl side group; Different third monomeric subunits.

In some embodiments, the first monomer subunit comprises a polymerized (meth)acrylate group and an aliphatic carbon moiety comprising at least two hydroxyl substituents. In some embodiments, the copolymer further comprises a fourth monomer subunit, different from the first, second and third monomer subunits, comprising polymerized (meth)acrylate groups and at least one alkoxyalkyl side group. . In some embodiments, the copolymer further comprises a monomer subunit that is a crosslinking subunit. In some embodiments, the aryloxy group of the second monomer subunit comprises a phenoxy group. In some embodiments, the aliphatic carbon moiety of the second monomer subunit is substituted with 1 hydroxyl group. In some embodiments, the halogen of the second monomer subunit is a bromo moiety. In some embodiments, the aliphatic carbon moiety of the second monomer subunit is a C ₃ moiety. In some embodiments, the aliphatic carbon moiety of the second monomer subunit is represented by -CH ₂ -CHOH-CH ₂ -. In some embodiments, the alkoxyalkoxyalkyl group of the third monomer subunit is a C ₃ to C ₁₂ group. In some embodiments, the alkoxyalkoxyalkyl group of the third monomer subunit comprises 2 oxygen atoms. In some embodiments, the alkoxyalkoxyalkyl group of the third monomer subunit is 2-ethoxyethoxyethyl. In some embodiments, the aliphatic carbon moiety comprising at least two hydroxyl substituents of the first monomer subunit consists of two hydroxyl substituents. In some embodiments, the aliphatic carbon moiety comprising at least two hydroxyl substituents of the first monomer subunit comprises a C ₂ to C ₆ aliphatic carbon moiety. In some embodiments, the first monomer subunit comprises 2,3-dihydroxypropyl methacrylate. In some embodiments, the alkoxyalkyl group of the fourth monomer subunit is a C ₃ to C ₁₂ group. In some embodiments, the alkoxyalkyl group of the fourth monomer subunit comprises a single oxygen atom. In some embodiments, the alkoxyalkyl group of the fourth monomer subunit is 2-ethoxyethyl. In some embodiments, the third monomer subunit comprises polymerized 2-ethoxyethoxyethyl methacrylate and the second monomer subunit comprises polymerized bromo-2-hydroxy-3-phenoxypropyl methacrylate. include rates.

In some embodiments, the first monomer subunit is about 30% to about 50% by weight of the copolymer composition, the second monomer subunit is about 20% to about 40% by weight of the copolymer composition, and the third monomer subunit is is from about 20% to about 40% by weight of the silver copolymer composition.

In some embodiments, the copolymer further comprises one or more of a UV absorber, an initiator, and/or a crosslinker. In some embodiments, the copolymer further comprises a monomer subunit that is a crosslinking subunit of a trimethacrylate crosslinking agent. In some embodiments, the copolymer has an equilibrium water content of at least 20 wt% in isotonic saline at 35°C. In some embodiments, the lens has a center thickness of at most 1 mm and unfolds in about 1 minute when placed in a saline solution at a temperature of 35°C. In some embodiments, the lens has a center thickness of at most 1 mm and unfolds in 5 to 20 seconds, preferably 5 to 10 seconds. In some embodiments, the refractive index at 546 nm and 20° C. is between about 1.47 and about 1.50. In some embodiments, the lens may be implanted through a tube having an internal diameter of approximately 1.6 mm. In some embodiments, the refractive index at 546 nm and 20° C. is greater than 1.47.

Some embodiments provide compositions comprising at least one copolymer comprising, for example: (a) (i) polymerized (meth)acrylate groups, and comprising at least two hydroxyl substituents; an aliphatic carbon moiety or (ii) a first monomer subunit comprising a polymerized (meth)acrylamide group, (b) a polymerized (meth)acrylate group, (i) an aryloxy moiety comprising at least one halogen and (ii) at least one side group comprising an aliphatic carbon moiety linking the aryloxy moiety with the polymerized (meth)acrylate group, wherein the aliphatic carbon moiety comprises at least one hydroxyl substituent. phosphorus, a second monomer subunit different from the first monomer subunit, (c) a third different from the first and second monomer subunits, comprising a polymerized (meth)acrylate group and at least one alkoxyalkoxyalkyl side group. a monomer subunit, and (d) optionally a fourth monomer subunit, different from the first, second and third monomer subunits, comprising polymerized (meth)acrylate groups and at least one alkoxyalkyl side group.

In some embodiments, the first monomer subunit comprises a polymerized (meth)acrylate group and an aliphatic carbon moiety comprising at least two hydroxyl substituents. In some embodiments, the copolymer further comprises a monomer subunit that is a crosslinking subunit. In some embodiments, the aryloxy group of the second monomer subunit comprises a phenoxy group. In some embodiments, the aliphatic carbon moiety of the second monomer subunit is substituted with 1 hydroxyl group. In some embodiments, the halogen of the second monomer subunit is a bromo moiety. In some embodiments, the alkoxyalkoxyalkyl group of the third monomer subunit is 2-ethoxyethoxyethyl. In some embodiments, the aliphatic carbon moiety comprising at least two hydroxyl substituents of the first monomer subunit consists of two hydroxyl substituents. In some embodiments, the aliphatic carbon moiety comprising at least two hydroxyl substituents of the first monomer subunit comprises a C ₂ to C ₆ aliphatic carbon moiety. In some embodiments, the first monomer subunit comprises 2,3-dihydroxypropyl methacrylate. In some embodiments, the alkoxyalkyl group of the fourth monomer subunit is 2-ethoxyethyl. In some embodiments, the third monomer subunit comprises polymerized 2-ethoxyethoxyethyl methacrylate and the second monomer subunit comprises polymerized bromo-2-hydroxy-3-phenoxypropyl methacrylate. include rates. In some embodiments, the first monomer subunit is about 30% to about 50% by weight of the copolymer composition, the second monomer subunit is about 20% to about 40% by weight of the copolymer composition, and the third monomer subunit is is from about 20% to about 40% by weight of the silver copolymer composition. In some embodiments, the copolymer further comprises one or more of a UV absorber, an initiator, and/or a crosslinker. In some embodiments, the copolymer further comprises a monomer subunit that is a crosslinking subunit of a trimethacrylate crosslinking agent. In some embodiments, the copolymer contains no more than 2 wt % of residual unreacted monomer before being subjected to a purification step. In some embodiments, the copolymer contains no more than 1 wt % of residual unreacted monomer before being subjected to a purification step. In some embodiments, the copolymer contains less than 1 wt % of residual unreacted monomer and is not subjected to a purification step. In some embodiments, the copolymer consists of first, second and third monomer subunits and optionally one or more of a fourth monomer subunit, a UV absorber, an initiator and/or a crosslinker. In some embodiments, the first monomer subunit comprises polymerized (meth)acrylamide groups.

Some embodiments include, for example, (a) an aliphatic carbon moiety comprising (i) polymerized (meth)acrylate groups and at least two hydroxyl substituents or (ii) (meth)acrylamide groups. a first monomer, (b) a (meth)acrylate group, (i) an aryloxy moiety comprising at least one halogen and (ii) an aliphatic carbon moiety connecting the aryloxy moiety to the (meth)acrylate group; a second monomer different from the first monomer, wherein the aliphatic carbon moiety comprises at least one hydroxyl substituent, (c) a (meth)acrylate group and at least one a third monomer, different from the first and second monomers, comprising an alkoxyalkoxyalkyl side group, (d) optionally a (meth)acrylate group, and a first, second and second monomer comprising at least one alkoxyalkyl side group. preparing a comonomer mixture comprising a fourth monomer different from the three monomers; A process for preparing a composition comprising at least one copolymer is provided, comprising polymerizing a comonomer mixture by adding a photoinitiator or a thermal initiator such as CGI 819 (light) and a Vazo type initiator.

In some embodiments, the initiator is a photoinitiator. In some embodiments, the copolymer contains no more than 2 wt % residual unreacted monomer after the polymerization step. In some embodiments, the copolymer contains no more than 1 wt % residual unreacted monomer after the polymerization step. In some embodiments, the comonomer mixture is solvent free. In some embodiments, the first monomer comprises an aliphatic carbon moiety comprising a (meth)acrylate group and at least two hydroxyl substituents. In some embodiments, the comonomer mixture further comprises a crosslinkable monomer. In some embodiments, the aryloxy group of the second monomer comprises a phenoxy group. In some embodiments, the aliphatic carbon moiety of the second monomer subunit is substituted with 1 hydroxyl group. In some embodiments, the halogen of the second monomer is a bromo moiety. In some embodiments, the alkoxyalkoxyalkyl group of the third monomer is 2-ethoxyethoxyethyl. In some embodiments, the aliphatic carbon moiety comprising at least two hydroxyl substituents of the first monomer comprises two hydroxyl substituents. In some embodiments, the aliphatic carbon moiety comprising at least two hydroxyl substituents of the first monomer comprises a C ₂ to C ₆ aliphatic carbon moiety. In some embodiments, the first monomer comprises 2,3-dihydroxypropyl methacrylate. In some embodiments, the alkoxyalkyl group of the fourth monomer is 2-ethoxyethyl. In some embodiments, the first monomer comprises 2-ethoxyethoxyethyl methacrylate and the second monomer comprises bromo-2-hydroxy-3-phenoxypropyl methacrylate. In some embodiments, the first monomer is about 20% to about 40% by weight of the comonomer composition, the second monomer is about 20% to about 40% by weight of the comonomer composition, and the third monomer is about 30% by weight of the comonomer composition. % to about 50% by weight. In some embodiments, the comonomer composition further comprises one or more of a UV absorber, an initiator, and/or a crosslinker. In some embodiments, the comonomer composition further comprises a monomer comprising a crosslinkable trimethacrylate.

At least one advantage of at least one embodiment includes higher refractive properties for an IOL, particularly for a hydrophilic index IOL.

At least one additional advantage of at least one embodiment includes superior unfolding properties for the IOL. For example, an IOL embodied herein can unfold in 5 to 10 seconds.

At least one additional advantage of at least one embodiment includes an absence of tacky properties after implantation of the IOL (eg, the haptic part does not stick to the optic part).

At least one additional advantage for at least one embodiment includes a refractive index greater than 1.47, 1.48, 1.49 or 1.50.

Yet another advantage to at least one embodiment is a high diopter IOL that can pass through a very small orifice injector, such as a 1.6 mm injector, eg, Medicel Accuject™ 1.6 mm.

Yet another advantage for at least one embodiment is an IOL having an Abbe value of 45 or greater.

All references cited herein are incorporated herein by reference in their entirety.

Intraocular lenses are generally known in the art. See, for example, US Patent Nos. 7,947,796; 7,387,642; 7,067,602; 6,517,750; and 6,267,784.

As used herein, the term “(meth)acrylate” refers to acrylic acid, esters, amides of acrylic or methacrylic acid, and other suitable derivatives of acrylic or methacrylic acid, and mixtures thereof. Illustrative examples of suitable (meth)acrylic monomers include, but are not limited to, the following methacrylate esters: methyl methacrylate, ethyl methacrylate, n-propyl methacrylate, n-butyl methacrylate (BMA), Isopropyl methacrylate, isobutyl methacrylate, n-amyl methacrylate, n-hexyl methacrylate, isoamyl methacrylate, 2-hydroxyethyl methacrylate, 2-hydroxypropyl methacrylate, N,N-dimethylaminoethyl methacrylate, N,N-diethylaminoethyl methacrylate, t-butylaminoethyl methacrylate, 2-sulfoethyl methacrylate, trifluoroethyl methacrylate, glycy Dill methacrylate (GMA), benzyl methacrylate, allyl methacrylate, 2-n-butoxyethyl methacrylate, 2-chloroethyl methacrylate, sec-butyl-methacrylate, tert-butyl methacrylate Late, 2-ethylbutyl methacrylate, cinnamyl methacrylate, crotyl methacrylate, cyclohexyl methacrylate, cyclopentyl methacrylate, 2-ethoxyethyl methacrylate, furfuryl methacrylate, hexa Fluoroisopropyl methacrylate, methallyl methacrylate, 3-methoxybutyl methacrylate, 2-methoxybutyl methacrylate, 2-nitro-2-methylpropyl methacrylate, n-octyl methacrylate , 2-ethylhexyl methacrylate, 2-phenoxyethyl methacrylate, 2-phenylethyl methacrylate, phenyl methacrylate, propargyl methacrylate, tetrahydrofurfuryl methacrylate and tetrahydropyranyl methacrylate. Examples of suitable acrylate esters include, but are not limited to, methyl acrylate, ethyl acrylate, n-propyl acrylate, isopropyl acrylate, n-butyl acrylate (BA), n-decyl acrylate, isobutyl acrylate , n-amyl acrylate, n-hexyl acrylate, isoamyl acrylate, 2-hydroxyethyl acrylate, 2-hydroxypropyl acrylate, N,N-dimethylaminoethyl acrylate, N,N-diethyl Aminoethyl acrylate, t-butylaminoethyl acrylate, 2-sulfoethyl acrylate, trifluoroethyl acrylate, glycidyl acrylate, benzyl acrylate, allyl acrylate, 2-n-butoxyethyl acrylate , 2-chloroethyl acrylate, sec-butyl-acrylate, tert-butyl acrylate, 2-ethylbutyl acrylate, cinnamyl acrylate, crotyl acrylate, cyclohexyl acrylate, cyclopentyl acrylate, 2- Ethoxyethyl acrylate, furfuryl acrylate, hexafluoroisopropyl acrylate, methallyl acrylate, 3-methoxybutyl acrylate, 2-methoxybutyl acrylate, 2-nitro-2-methylpropyl acrylate , n-octyl acrylate, 2-ethylhexyl acrylate, 2-phenoxyethyl acrylate, 2-phenylethyl acrylate, phenyl acrylate, propargyl acrylate, tetrahydrofurfuryl acrylate and tetrahydropyranyl Contains acrylate.

One embodiment provides a hydrophilic intraocular lens comprising at least one copolymer comprising:

(a) a first monomer subunit comprising (i) an aliphatic carbon moiety comprising polymerized (meth)acrylate groups and at least two hydroxyl substituents or (ii) polymerized (meth)acrylamide groups;

(b) a polymerized (meth)acrylate group, (i) an aryloxy moiety comprising at least one halogen and (ii) an aliphatic carbon moiety connecting the aryloxy moiety with the polymerized (meth)acrylate group; a second monomer subunit different from the first monomer subunit, wherein the second monomer subunit comprises at least one side group comprising: wherein the aliphatic carbon moiety comprises at least one hydroxyl substituent;

(c) a third monomer subunit, different from the first and second monomer subunits, comprising polymerized (meth)acrylate groups and at least one alkoxyalkoxyalkyl side group.

first monomeric subunit

The first monomer subunit is derived from a hydrophilic monomer. In some embodiments, it may be the monomer subunit present in the maximum amount as measured by weight percent on the copolymer or in an amount equal to the other of the first three monomer subunits as measured by weight percent on the copolymer. The first monomer subunit comprises a polymerizable moiety such as acrylate, methacrylate, acrylamide and/or methacrylamide.

In some embodiments, the first monomer subunit also comprises at least 1 carbon moiety comprising at least 2 hydroxyl substituents, for example 2, 3, 4 hydroxyl substituents. The first monomer subunit may include a hydrophilic monomer subunit suitable for a foldable IOL. In some embodiments, the at least one carbon moiety comprising at least 2 hydroxyl substituents is a C2-C5 alkyl moiety comprising or consisting of 2, 3, 4 hydroxyl substituents. Examples include dihydroxypropyl (eg 2,3-dihydroxypropyl), dihydroxybutyl (eg 2,3-dihydroxybutyl, 2,4-dihydroxybutyl, 3, 4-dihydroxybutyl) and the like, but are not limited thereto.

In another embodiment, the first monomer subunit comprises polymerized (meth)acrylamide groups. Examples include, but are not limited to, N,N-dimethyl(meth)acrylamide, ethoxyethyl(meth)acrylamide, acrylamide, dihydroxypropyl acrylamide, hydroxy ethyl acrylamide, hydroxy methyl acrylamide. don't In another embodiment, the first monomer subunit comprising polymerized (meth)acrylamide groups also comprises a C1-C5 alkyl moiety. In some embodiments, the first monomer subunit also comprising a polymerized (meth)acrylamide group is a C1-C5 alkyl moiety and one or more hydroxyl substituents, for example 1, 2, 3, 4 hydroxyl substituents Include (s)

second monomeric subunit

The second monomer subunit can be the monomer subunit present in the second largest amount as measured by weight percent relative to the copolymer or in an amount equivalent to the first monomer as measured as weight percent relative to the copolymer. This subunit contains polymerizable moieties such as acrylates, methacrylates, acrylamides and/or methacrylamides. The subunit also includes an aliphatic spacer comprising one or more hydroxyl moieties. Finally, the second monomer subunit comprises an optionally substituted aryl or aryloxy moiety comprising at least one halogen such as for example F, Cl, Br and/or I. In another embodiment, the second monomer subunit comprising polymerized acrylate or methacrylate groups may instead contain polymerized acrylamide or methacrylamide groups optionally substituted at nitrogen by hydrogen or C ₁ to C ₅ alkyl. can include In some embodiments, the second monomer subunit comprises polymerized methacrylate groups.

For example, an aryloxyalkyl methacrylate monomer subunit can be represented by the formula Ar-OR ₁ -MA, where Ar is an optionally substituted aryl compound such as, for example, an optionally substituted phenyl, and R ₁ is an aliphatic spacer such as a divalent alkyl group and "MA" is a methacrylate. Alternatively, the aryloxyalkyl acrylate monomer subunit may be represented by the formula Ar-OR ₂ -A, wherein Ar is an optionally substituted aryl compound such as, for example, an optionally substituted phenyl, and R ₂ is aliphatic A spacer such as a divalent alkyl group and "A" is an acrylate. Likewise, an aryloxyalkyl acrylamide monomer subunit may be represented by the formula Ar-OR ₃ -AA, wherein Ar is an optionally substituted aryl compound such as, for example, an optionally substituted phenyl, and R ₃ is an aliphatic spacer For example, a divalent alkyl group and “AA” is acrylamide. An aryloxyalkyl methacrylamide monomer subunit may also be represented by the formula Ar-OR ₄ -MAA, wherein Ar is an optionally substituted aryl compound such as, for example, an optionally substituted phenyl, and R ₄ is an aliphatic spacer For example, a divalent alkyl group and “MAA” is methacrylamide. The divalent groups R ₁ , R ₂ , R ₃ , and R ₄ may be further substituted with at least one hydroxy group. AA or MAA monomer subunits may be optionally substituted on nitrogen by hydrogen or C ₁ to C ₅ alkyl. Examples of C ₁ to C ₅ alkyl include methyl, ethyl, propyl, butyl, pentyl and isomers thereof.

Both hydroxy and halogen-substituted aryloxyalkyl methacrylates and hydroxy and halogen-substituted aryloxyalkyl acrylates are ester-containing monomeric compounds, as recognized by those skilled in the art. Likewise, those skilled in the art will recognize hydroxy and halogen-substituted aryloxyalkyl acrylamides and hydroxy and halogen-substituted aryloxyalkyl methacrylamides as amide-containing monomeric compounds.

In some embodiments, R ₁ , R ₂ , R ₃ and R ₄ are independently hydroxy-substituted alkyls having 1 to 5 carbon atoms and in some embodiments 1, 2, 3, 4 or 5 carbon atoms. groups, wherein the alkyl groups are substituted with one or more hydroxy groups. Regarding R ₁ , it will be understood that the hydroxy-substituted alkyl group is bonded to the O of the Ar—O group and also to the O atom of the MA group. Similarly, with respect to R ₂ , it will be appreciated that the hydroxy-substituted alkyl group is bonded to the O of the Ar—O group and also to the O atom of the A group. Similarly, with respect to R ₃ , it will be appreciated that the hydroxy-substituted alkyl group is bonded to the O of the Ar-O group and also to the N atom of the AA group. Similarly, with respect to R ₄ , it will be appreciated that the hydroxy-substituted alkyl group is bonded to the O of the Ar—O group and also to the N atom of the MAA group. A hydroxy group may be substituted on any carbon of an alkyl group. Hydroxy-substituted alkyl groups that may be used in accordance with embodiments herein include straight chain alkyl groups including, but not limited to, methyl, ethyl, propyl, butyl and pentyl groups, wherein at least one CH is substituted with C-OH . Alkyl groups may also include branched chain isomers of straight chain alkyl groups including, but not limited to, the following, which are provided by way of example only: -CH(CH ₃ ) ₂ , -CH(CH ₃ )(CH ₂ CH ₃ ) , -CH(CH ₂ CH ₃ ) ₂ , -C(CH ₃ ) ₃ , etc., wherein at least one CH is substituted with C-OH. In some embodiments, the hydroxy-substituted aryloxyalkyl methacrylate or hydroxy-substituted aryloxyalkyl acrylate is selected from R ₁ and R ₂ having 1, 2, 3 or 4 carbon atoms. .

Specific embodiments of R ₁ , R ₂ , R ₃ , and R ₄ are non-limiting examples and the like. AA or MAA monomer subunits may be optionally substituted on nitrogen by hydrogen or C ₁ to C ₅ alkyl.

It will be recognized by those skilled in the art that an aryloxy group includes an aryl compound bonded to an oxygen atom. In some embodiments, aryl groups include optionally substituted phenyl or naphthyl. In some embodiments, an aryl group can include one or more heteroatoms, such as nitrogen or sulfur, as non-limiting examples. Aryl moieties may be optionally substituted by one or more alkyl groups including, but not limited to, methyl, ethyl, propyl, butyl and pentyl groups. Alkyl groups can be branched-chain isomers of straight-chain alkyl groups. The aryl moiety may be optionally substituted by one or more alkoxy groups including alkyl groups bound to oxygen atoms, which alkyl groups include but are not limited to methyl, ethyl, propyl, butyl and/or pentyl groups. Alkyl groups can be branched-chain isomers of straight-chain alkyl groups. Additionally the aryl moiety is substituted by one or more halogen groups such as F, Cl, Br and/or I. In some embodiments, an aryl moiety is substituted by 1 halogen. In some embodiments, the aryl moiety is substituted by 2, 3, 4 or 5 halogens. In some embodiments where the aryl moiety is substituted by at least two halogens, the halogens can be the same or different.

Some specific hydroxy and halogen-substituted aryloxyalkyl methacrylates, hydroxy and halogen-substituted aryloxyalkyl acrylates, hydroxy and halogen-substituted aryloxyalkyl methacrylamides and hydrogels useful in forming copolymers Examples of hydroxy and halogen-substituted aryloxyalkyl acrylamide monomer subunits include 2-bromo-2-hydroxy-3-phenoxypropyl acrylate, 3-bromo-2-hydroxy-3-phenoxypropyl Acrylate, 4-bromo-2-hydroxy-3-phenoxypropyl acrylate, 2-bromo-2-hydroxy-3-phenoxypropyl methacrylate, 3-bromo-2-hydroxy- 3-phenoxypropyl methacrylate, 4-bromo-2-hydroxy-3-phenoxypropyl methacrylate, 2-bromo-2-hydroxy-3-phenoxypropyl acrylamide, 3-bromo -2-hydroxy-3-phenoxypropyl acrylamide, 4-bromo-2-hydroxy-3-phenoxypropyl acrylamide and/or 2-bromo-2-hydroxy-3-phenoxypropyl meth Crylamide, 3-bromo-2-hydroxy-3-phenoxypropyl methacrylamide or 4-bromo-2-hydroxy-3-phenoxypropyl methacrylamide. In some embodiments, the second monomer comprises bromo-2-hydroxy-3-phenoxypropyl methacrylate (BrHPPMA).

In some embodiments, the copolymers of the present invention may also include a second monomer represented by formula (II), wherein R' is hydrogen or methyl, Y is O or -NR", and X is H , Cl, Br, -CH ₃ or -OCH ₃ , n is 1 to 6, m is 1 to 6, R″ is hydrogen or C ₁ to C ₅ alkyl; Z is H, OH or a halogen group.

In another embodiment, n and m are 1 or 2, X is Br, Z is H, Y is O and q is 1, 2, 3, 4 or 5. In some embodiments q is 1 or 2.

Thus, one preferred embodiment provides an intraocular lens in which the second monomer subunit comprises polymerized (meth)acrylate groups. In another embodiment, the aryloxy group includes a phenoxy group. In another embodiment, the aryloxy group includes an unsubstituted phenoxy group. In another embodiment, the aliphatic carbon moiety of the second monomer is substituted with 1 hydroxyl group. In another embodiment, the aliphatic carbon moiety of the second monomer is a C ₃ moiety. In another embodiment, the aliphatic carbon moiety of the second monomer is represented by -CH(Br)-CHOH-CH ₂ -. Finally, in one embodiment, the side group of the second monomer comprises -CH(Br)-CHOH-CH ₂ -OPh, wherein OPh is an unsubstituted phenoxy group.

3rd monomeric subunit

The third monomer subunit comprises a polymerizable moiety such as acrylate, methacrylate, acrylamide and/or methacrylamide. The subunit also includes an alkoxyalkoxyalkyl side group. The third monomer subunit may include a monomer subunit suitable for a foldable IOL. Examples include, but are not limited to, alkoxyalkoxyalkyl (meth)acrylates or alkoxyalkoxy (meth)acrylamides.

In another embodiment, the third monomer subunit comprising polymerized acrylate or methacrylate groups may instead contain polymerized acrylamide or methacrylamide groups optionally substituted at nitrogen by hydrogen or C ₁ to C ₅ alkyl. can include In some embodiments, the third monomer subunit comprises polymerized methacrylate groups.

An alkoxyalkoxyalkyl methacrylate monomer subunit may be represented by the formula R ₁₅ -OR ₅ -OR ₆ -MA, wherein R ₅ , R ₆ , R ₁₅ are an alkyl group and “MA” is a methacrylate. An alkoxyalkoxyalkyl acrylate monomer subunit may be represented by the formula R ₂₀ -OR ₇ -OR ₈ -A, wherein R ₇ , R ₈ , R ₂₀ are alkyl groups and “A” is an acrylate. Both alkoxyalkoxyalkyl methacrylates and alkoxyalkoxyalkyl acrylates are ester-containing monomeric compounds, as recognized by those skilled in the art. In some embodiments, R ₅ to R ₈ , R ₁₅ and R ₂₀ can be independently selected from alkyl groups having 1 to 5 carbon atoms and in some embodiments 1, 2, 3, 4 or 5 carbon atoms. have. Regarding R ₆ , it will be understood that the alkyl group is bonded to the O of the R ₅ -O group and also to the O atom of the MA group. Similarly, with respect to R ₈ , it will be understood that the alkyl group is bonded to the O of the R ₇ —O group and also to the O atom of the A group. Alkyl groups that may be used in accordance with embodiments herein include straight chain alkyl groups including, but not limited to, methyl, ethyl, propyl, butyl and pentyl groups. Alkyl groups may also include branched chain isomers of straight chain alkyl groups including, but not limited to, the following, which are provided by way of example only: -CH(CH ₃ ) ₂ , -CH(CH ₃ )(CH ₂ CH ₃ ) , -CH(CH ₂ CH ₃ ) ₂ , -C(CH ₃ ) ₃ , and the like. In some embodiments, the alkoxyalkoxyalkyl methacrylate or alkoxyalkoxyalkyl acrylate is selected from R ₅ to R ₈ , R ₁₅ , and R ₂₀ having 1, 2, 3 or 4 carbon atoms. Examples of some specific alkoxyalkoxyalkyl methacrylate and alkoxyalkoxyalkyl acrylate monomer subunits useful in forming the copolymers of embodiments herein are methoxymethoxyethyl methacrylate, ethoxyethoxyethyl methacrylate, pro Poxypropoxyethyl methacrylate, butoxybutoxymethyl methacrylate, methoxymethoxypropyl methacrylate, ethoxyethoxypropyl methacrylate, propoxypropoxypropyl methacrylate, butoxybutoxypropyl methacrylate acrylate, methoxymethoxybutyl methacrylate, ethoxyethoxybutyl methacrylate, propoxypropoxybutyl methacrylate, butoxybutoxybutyl methacrylate, methoxymethoxyethyl acrylate, ethoxy Toxyethyl acrylate, propoxypropoxyethyl acrylate, butoxybutoxymethyl acrylate, methoxymethoxypropyl acrylate, ethoxyethoxypropyl acrylate, propoxypropoxypropyl acrylate, butoxybutoxypropyl acrylate, methoxymethoxybutyl acrylate, ethoxyethoxybutyl acrylate, propoxypropoxybutyl acrylate and butoxybutoxybutyl acrylate. In some preferred embodiments, the copolymer comprises ethoxyethoxyethyl methacrylate (EOEOEMA).

Accordingly, a particularly preferred embodiment provides an intraocular lens wherein the alkoxyalkoxyalkyl group is a C ₃ to C ₁₂ group. In one embodiment, the alkoxyalkoxyalkyl group comprises 2 oxygen atoms. In a specific embodiment, the alkoxyalkoxyalkyl group is 2-ethoxyethoxyethyl.

optional fourth monomeric subunit

In some embodiments, the copolymer may comprise a fourth monomer subunit different from the first, second and third monomer subunits comprising polymerized (meth)acrylate groups and one alkoxyalkyl side group.

Examples of such monomer subunits used to prepare the fourth monomer subunit include alkoxyalkyl methacrylate and/or alkoxyalkyl acrylate monomer subunits. In some embodiments, the fourth monomer subunit comprises polymerized (meth)acrylate groups and contains 1 alkoxyalkyl side group. An alkoxyalkyl methacrylate monomer subunit may be represented by the formula R ₅ -OR ₆ -MA, wherein R ₅ and R ₆ are alkyl groups and “MA” is methacrylate. An alkoxyalkyl acrylate monomer subunit may be represented by the formula R ₇ -OR ₈ -A, wherein R ₇ and R ₈ are alkyl groups and “A” is an acrylate. Both alkoxyalkyl methacrylates and alkoxyalkyl acrylates are ester-containing monomeric compounds, as recognized by those skilled in the art. In some embodiments, R ₅ to R ₈ can be independently selected from alkyl groups having 1 to 5 carbon atoms and in some embodiments 1, 2, 3, 4 or 5 carbon atoms. Regarding R ₆ , it will be understood that the alkyl group is bonded to the O of the R ₅ -O group and also to the O atom of the MA group. Similarly, with respect to R ₈ , it will be understood that the alkyl group is bonded to the O of the R ₇ —O group and also to the O atom of the A group. Alkyl groups that may be used in accordance with embodiments herein include straight chain alkyl groups including, but not limited to, methyl, ethyl, propyl, butyl and pentyl groups. Alkyl groups may also include branched chain isomers of straight chain alkyl groups including, but not limited to, the following, which are provided by way of example only: -CH(CH ₃ ) ₂ , -CH(CH ₃ )(CH ₂ CH ₃ ) , -CH(CH ₂ CH ₃ ) ₂ , -C(CH ₃ ) ₃ , and the like. In some embodiments, the alkoxyalkyl methacrylate or alkoxyalkyl acrylate is selected from R ₅ to R ₈ having 1, 2, 3 or 4 carbon atoms. Examples of some specific alkoxyalkyl methacrylate and alkoxyalkyl acrylate monomer subunits useful in forming the copolymers of embodiments herein include methoxyethyl methacrylate, ethoxyethyl methacrylate, propoxyethyl methacrylate, Butoxymethyl Methacrylate, Methoxypropyl Methacrylate, Ethoxypropyl Methacrylate, Propoxypropyl Methacrylate, Butoxypropyl Methacrylate, Methoxybutyl Methacrylate, Ethoxybutyl Methacrylate, Pro Poxybutyl methacrylate, butoxybutyl methacrylate, methoxyethyl acrylate, ethoxyethyl acrylate, propoxyethyl acrylate, butoxymethyl acrylate, methoxypropyl acrylate, ethoxypropyl acrylate, pro but is not limited to, poxypropyl acrylate, butoxypropyl acrylate, methoxybutyl acrylate, ethoxybutyl acrylate, propoxybutyl acrylate and butoxybutyl acrylate. In some preferred embodiments, the copolymer comprises ethoxyethyl methacrylate (EOEMA).

Accordingly, a particularly preferred embodiment provides an intraocular lens wherein the alkoxyalkyl group is a C ₃ to C ₁₂ group. In one embodiment, an alkoxyalkyl group contains a single oxygen atom. In some embodiments, an alkoxyalkyl group is not a repeating alkoxyalkyl group. In a specific embodiment, the alkoxyalkyl group is 2-ethoxyethyl.

In some embodiments, alkoxyalkyl methacrylate and/or alkoxyalkyl acrylate monomer subunits are used in copolymers disclosed herein to produce copolymers with higher glass transition temperatures.

In some embodiments, copolymers provided herein do not include a fourth monomer subunit.

optional fifth monomeric subunit

In some embodiments, the copolymer is a polymerizable moiety, such as an acrylate, methacrylate, acrylamide and/or methacrylamide, different from the first, second, third and fourth monomer subunits. May contain 5 monomeric subunits. The subunit also includes an aliphatic spacer comprising one or more hydroxyl moieties. Finally, the fifth monomeric subunit comprises an optionally substituted aryl or aryloxy moiety. In another embodiment, the fifth monomer subunit comprising polymerized acrylate or methacrylate groups may instead contain polymerized acrylamide or methacrylamide groups optionally substituted at nitrogen by hydrogen or C ₁ to C ₅ alkyl. can include In some embodiments, the fifth monomer subunit comprises polymerized methacrylate groups.

For example, an aryloxyalkyl methacrylate monomer subunit can be represented by the formula Ar-OR ₁ -MA, where Ar is an optionally substituted aryl compound such as, for example, an optionally substituted phenyl, and R ₁ is an aliphatic spacer such as a divalent alkyl group and "MA" is a methacrylate. Alternatively, the aryloxyalkyl acrylate monomer subunit may be represented by the formula Ar-OR ₂ -A, wherein Ar is an optionally substituted aryl compound such as, for example, an optionally substituted phenyl, and R ₂ is aliphatic A spacer such as a divalent alkyl group and "A" is an acrylate. Likewise, an aryloxyalkyl acrylamide monomer subunit may be represented by the formula Ar-OR ₃ -AA, wherein Ar is an optionally substituted aryl compound such as, for example, an optionally substituted phenyl, and R ₃ is an aliphatic spacer For example, a divalent alkyl group and “AA” is acrylamide. An aryloxyalkyl methacrylamide monomer subunit may also be represented by the formula Ar-OR ₄ -MAA, wherein Ar is an optionally substituted aryl compound such as, for example, an optionally substituted phenyl, and R ₄ is an aliphatic spacer For example, a divalent alkyl group and “MAA” is methacrylamide. The divalent groups R ₁ , R ₂ , R ₃ , and R ₄ may be further substituted by at least one hydroxy group. AA or MAA monomer subunits may be optionally substituted on nitrogen by hydrogen or C ₁ to C ₅ alkyl. Examples of C ₁ to C ₅ alkyl include methyl, ethyl, propyl, butyl, pentyl and isomers thereof.

Both hydroxy-substituted aryloxyalkyl methacrylates and hydroxy-substituted aryloxyalkyl acrylates are ester-containing monomeric compounds, as recognized by those skilled in the art. Likewise, those skilled in the art will recognize hydroxy-substituted aryloxyalkyl acrylamides and hydroxy-substituted aryloxyalkyl methacrylamides as amide-containing monomeric compounds. In some embodiments, R ₁ , R ₂ , R ₃ and R ₄ are independently hydroxy-substituted alkyls having 1 to 5 carbon atoms and in some embodiments 1, 2, 3, 4 or 5 carbon atoms. groups, wherein the alkyl groups are substituted by one or more hydroxy groups. Regarding R ₁ , it will be understood that the hydroxy-substituted alkyl group is bonded to the O of the Ar—O group and also to the O atom of the MA group. Similarly, with respect to R ₂ , it will be appreciated that the hydroxy-substituted alkyl group is bonded to the O of the Ar—O group and also to the O atom of the A group. Similarly, with respect to R ₃ , it will be appreciated that the hydroxy-substituted alkyl group is bonded to the O of the Ar-O group and also to the N atom of the AA group. Similarly, with respect to R ₄ , it will be appreciated that the hydroxy-substituted alkyl group is bonded to the O of the Ar—O group and also to the N atom of the MAA group. A hydroxy group may be substituted on any carbon of an alkyl group. Hydroxy-substituted alkyl groups that may be used in accordance with embodiments herein include straight chain alkyl groups including, but not limited to, methyl, ethyl, propyl, butyl and pentyl groups, wherein at least one CH is substituted with C-OH. Alkyl groups may also include branched chain isomers of straight chain alkyl groups including, but not limited to, the following, which are provided by way of example only: -CH(CH ₃ ) ₂ , -CH(CH ₃ )(CH ₂ CH ₃ ) , -CH(CH ₂ CH ₃ ) ₂ , -C(CH ₃ ) ₃ , etc., wherein at least one CH is substituted with C-OH. In some embodiments, the hydroxy-substituted aryloxyalkyl methacrylate or hydroxy-substituted aryloxyalkyl acrylate is selected from R ₁ and R ₂ having 1, 2, 3 or 4 carbon atoms. . Specific embodiments of R ₁ , R ₂ , R ₃ , and R ₄ include, but are not limited to, 1-hydroxy propyl, 2-hydroxy propyl, 3-hydroxy propyl, 2-hydroxy butyl, 3-hydroxy propyl oxy butyl, 2,3-dihydroxy butyl and the like. AA or MAA monomer subunits may be optionally substituted on nitrogen by hydrogen or C ₁ to C ₅ alkyl.

It will be recognized by those skilled in the art that an aryloxy group includes an aryl compound bonded to an oxygen atom. In some embodiments, aryl groups include optionally substituted phenyl or naphthyl. In some embodiments, an aryl group can include one or more heteroatoms, such as nitrogen or sulfur, as non-limiting examples. Aryl moieties may be optionally substituted by one or more alkyl groups including, but not limited to, methyl, ethyl, propyl, butyl and pentyl groups. Alkyl groups can be branched-chain isomers of straight-chain alkyl groups. The aryl moiety may be optionally substituted by one or more alkoxy groups including alkyl groups bound to oxygen atoms, which alkyl groups include but are not limited to methyl, ethyl, propyl, butyl and/or pentyl groups. Alkyl groups can be branched-chain isomers of straight-chain alkyl groups.

Some specific hydroxy-substituted aryloxyalkyl methacrylates, hydroxy-substituted aryloxyalkyl acrylates, hydroxy-substituted aryloxyalkyl methacrylamides and hydroxy-substituted aryloxy useful in forming copolymers Examples of alkyl acrylamide monomer subunits are 2-hydroxy-3-phenoxypropyl acrylate, 2-hydroxy-3-phenoxypropyl methacrylate, 2-hydroxy-3-phenoxypropyl acrylamide and/or or 2-hydroxy-3-phenoxypropyl methacrylamide. In some embodiments, the first monomer comprises 2-hydroxy-3-phenoxypropyl methacrylate (HPPMA).

In some embodiments, the copolymers of the present invention may also include a fifth monomer represented by formula (I) wherein R' is hydrogen or methyl, Y is O or -NR", and X is H , -CH ₃ or -OCH ₃ , n is 1 to 6, and R″ is hydrogen or C ₁ to C ₅ alkyl.

In other embodiments, n is 1 or 2, X is hydrogen, and Y is O.

Accordingly, one preferred embodiment provides an intraocular lens wherein the fifth monomer subunit comprises polymerized (meth)acrylate groups. In another embodiment, the aryloxy group includes a phenoxy group. In another embodiment, the aryloxy group includes an unsubstituted phenoxy group. In another embodiment, the aliphatic carbon moiety of the fifth monomer subunit is substituted with 1 hydroxyl group. In another embodiment, the aliphatic carbon moiety of the fifth monomer subunit is a C ₃ moiety. In another embodiment, the aliphatic carbon moiety of the fifth monomer subunit is represented by -CH ₂ -CHOH-CH ₂ -. Finally, in one embodiment, the side group of the fifth monomer subunit comprises -CH ₂ -CHOH-CH ₂ -OPh, wherein OPh is an unsubstituted phenoxy group.

In some embodiments, copolymers provided herein do not include a fifth monomer subunit.

Crosslinking agent (sixth monomer)

The intraocular lens may comprise a copolymer further comprising a crosslinked sixth monomeric subunit. In particular, di- or trifunctional cross-linking agents may be used to form cross-linking subunits. However, other di- or polyfunctional cross-linking agents known in the art may also be used instead of, or in addition to, di- or tri-functional cross-linking agents.

Copolymers can be prepared using conventional polymerization techniques known to those skilled in the art of polymer chemistry. A crosslinking agent may be used in the polymerization reaction. For example, any crosslinking or bifunctional monomer may be used in an effective amount to obtain the desired crosslinking density. For example, concentrations ranging from 0 to about 10 weight percent, such as from about 0.01 to about 4 weight percent, or in some embodiments from 0.5 to 3 weight percent, based on the weight of the polymer. Examples of suitable crosslinkers include di-olefin functional components or ethylene glycol dimethacrylate (EGDMA), diethylene glycol dimethacrylate (“DEGDMA”), triethylene glycol dimethacrylate, and the like. Generally, crosslinkers help improve the dimensional stability of the resulting copolymer.

In some embodiments, the composition includes at least one crosslinking agent having a polymerization functionality of three or more (multifunctional crosslinking agent). An example of a multifunctional crosslinker includes, but is not limited to, trimethylol propane trimethacrylate (TMPTMA). Similar acrylate crosslinkers, such as trimethylol propane triacrylate, may also be used in place of or in combination with any of their methacrylate analogues. Some embodiments include two or more trifunctional or multifunctional crosslinking agents and bifunctional crosslinking agents known in the art or incorporated herein by reference, such as EGDMA or DEGDMA. Thus, in some embodiments, the copolymer composition includes EGDMA, DEGDMA and/or TMPTMA. In some such embodiments, the amount of EGDMA and/or TMPTMA ranges from about 0.5 to about 5 (eg, from about 2 to about 3 or from about 2.5 to about 3) weight percent based on the weight of the dry copolymer.

In one embodiment, the only crosslinking agent used is a trifunctional crosslinking agent, such as a trifunctional methacrylate crosslinking agent.

Examples of specific copolymers useful in embodiments of the present invention are discussed in the Examples, wherein all weights are in grams.

composition/amount

The copolymers described herein contain as major components, measured on a weight basis, the first and second monomer subunits such as alkoxyalkoxyalkyl methacrylates, alkoxyalkoxyalkyl acrylates, hydroxy and halogen-substituted aryloxyalkyl methacrylates. hydroxy and halogen-substituted aryloxyalkyl acrylate monomer subunits, and third and fourth monomer subunits as minor components.

weight amount

In some embodiments, copolymers provided herein may comprise from about 20 to 60 percent, eg, from about 30 percent to about 50 weight percent of the first monomer subunits, based on the total weight of the copolymer. In some embodiments, the first monomer subunit comprises about 30-40 percent, about 40-50 percent, or about 50-60 weight percent of the copolymer. In some embodiments, the first monomer subunit comprises about 35-40 percent, about 40-45 percent, or about 45-50 weight percent of the copolymer. In some embodiments, the first monomer subunit comprises about 40 percent, about 41 percent, about 42 percent, about 43 percent, about 44 percent, about 45 percent, about 46 percent, about 47 percent, about 48 percent, It accounts for about 49 percent and about 50 percent by weight.

In some embodiments, the first monomer subunit can include a hydrophilic monomer subunit. In some embodiments, the hydrophilic monomer subunit comprises GMA. In other embodiments, the first monomer subunit may include one or two or more different monomer subunits, such as Am, DMA, EOEAm, HEAm, and the like.

Without limiting the scope of the present invention by theory, the presence of the first monomer subunit provides a high water content as detailed elsewhere in this disclosure.

In some embodiments, copolymers provided herein can include from about 10 percent to about 40 weight percent of the second monomer subunit, based on the total weight of the copolymer. In some embodiments, the second monomer subunit comprises about 15-35 weight percent of the copolymer. In some embodiments, the second monomer subunit comprises about 15-20 percent, about 20-25 percent, about 25-30 percent, about 30-35 percent, or about 35-40 weight percent of the copolymer. In some embodiments, the second monomer subunit comprises about 20 percent, about 21 percent, about 22 percent, about 23 percent, about 24 percent, about 25 percent, about 26 percent, about 27 percent, about 28 percent, about 29 percent, about 30 percent, about 31 percent, about 32 percent, about 33 percent, about 34 percent, about 35 percent, about 36 percent, about 37 percent, about 38 percent, about 39 percent, or about 40 percent by weight do.

In some embodiments, the second monomer subunit comprises BrHPPMA.

In the copolymers of the present invention, measured on a weight basis, the total amount of one or more of the first and second monomer subunits may make up the majority of the copolymer. For example, in some embodiments, any of the alkoxyalkoxyalkyl methacrylates, alkoxyalkoxyalkyl acrylates, hydroxy and halogen-substituted aryloxyalkyl methacrylates and hydroxy and halogen-substituted aryloxyalkyl acrylates The total amount of the combined amounts of monomer subunits may be from about 55 percent to about 95 weight percent based on the total weight of the copolymer. In some embodiments, the first and second monomer subunits may comprise about 55-60 percent, about 55-65 percent, about 55-70 percent, about 55-75 percent, or about 55-80 percent by weight of the copolymer. have. In some embodiments, the first and second monomer subunits may comprise about 55-65 percent, or about 65-75 weight percent of the copolymer. In some embodiments, the first and second monomer subunits comprise about 55 percent, about 56 percent, about 57 percent, about 58 percent, about 59 percent, about 60 percent, about 61 percent, about 62 percent, about 63 percent, about 64 percent, about 65 percent, about 66 percent, about 67 percent, about 68 percent, about 69 percent, about 70 percent, about 71 percent, about 72 percent, about 73 percent, about 74 percent, about 75 percent , about 76 percent, about 77 percent, about 78 percent, about 79 percent or about 80 percent by weight.

In some embodiments, copolymers provided herein can include from about 20 to about 40 weight percent of the third monomer subunit, based on the total weight of the copolymer. In some embodiments, the third monomer subunit comprises about 20 percent, about 21 percent, about 22 percent, about 23 percent, about 24 percent, about 25 percent, about 26 percent, about 27 percent, about 28 percent, about 29 percent, about 30 percent, about 31 percent, about 32 percent, about 33 percent, about 34 percent, about 35 percent, about 36 percent, about 37 percent, about 38 percent, about 39 percent, or about 40 percent by weight do.

In the copolymers of the present invention, the total amount of one or more of the third monomer subunits will make up a minority of the polymer when measured on a weight basis.

In some embodiments, copolymers provided herein can include from about 0 to 15 weight percent of the fourth monomer subunit, based on the total weight of the copolymer. In some embodiments, the fourth monomer subunit may comprise about 5 to 10 percent or about 7 to 10 weight percent of the copolymer. In some embodiments, the fourth monomer subunit comprises about 5 percent, about 6 percent, about 7 percent, about 8 percent, about 9 percent, about 10 percent, about 11 percent, about 12 percent, about 13 percent of the copolymer, about 14 percent or about 15 percent by weight. In some embodiments, the fourth monomer subunit may account for about 7.5 weight percent of the copolymer.

In some embodiments, copolymers provided herein can include about 0 weight percent of the fourth monomer subunit, based on the total weight of the copolymer.

In some embodiments, copolymers provided herein can include about 0-25 weight percent of the fifth monomer subunit, based on the total weight of the copolymer. In some embodiments, the fifth monomer subunit may comprise about 0-10 percent, about 0-15 percent, or about 0-20 weight percent of the copolymer. In some embodiments, the fifth monomer subunit comprises about 0 percent, about 1 percent, about 2 percent, about 3 percent, about 4 percent, about 5 percent, about 6 percent, about 7 percent, about 8 percent, About 9 percent, about 10 percent, about 11 percent, about 12 percent, about 13 percent, about 14 percent, about 15 percent, about 16 percent, about 17 percent, about 18 percent, about 19 percent, about 20 percent, about 21 percent, about 22 percent, about 23 percent, about 24 percent or about 25 percent by weight. In some embodiments, the fifth monomer subunit may account for about 20 weight percent of the copolymer.

In some embodiments, the fifth monomeric subunit is EOEMA. In some embodiments, copolymers provided herein can include about 0 weight percent of the fifth monomer subunit, based on the total weight of the copolymer.

In the copolymers of the present invention, the total amount of one or more of the crosslinking monomer subunits will make up the minority of the copolymer. For example, in some embodiments, the total amount of the combined amount of incorporated crosslinking monomer subunits ranges from about 0.5 percent to 3.0 weight percent, based on the total weight of the copolymer. In some embodiments, the crosslinking monomer subunit may comprise about 0.5-1.0 percent, about 0.5-1.5 percent, about 0.5-2.0 percent or about 0.5-2.5 weight percent of the copolymer. In some embodiments, the crosslinking monomer subunit comprises about 0.5 percent, about 0.6 percent, about 0.7 percent, about 0.8 percent, about 0.9 percent, about 1.0 percent, about 1.1 percent, about 1.2 percent, about 1.3 percent, about 1.4 percent, about 1.5 percent, about 1.6 percent, about 1.7 percent, about 1.8 percent, about 1.9 percent, about 2.0 percent, about 2.1 percent, about 2.2 percent, about 2.3 percent, about 2.4 percent, about 2.5 percent, about 2.6 percent , about 2.7 percent, about 2.8 percent, about 2.9 percent or about 3.0 percent by weight. In some embodiments, crosslinking monomer subunits may account for about 2.74 weight percent of the copolymer.

In some embodiments, the crosslinking monomeric subunit comprises TMPTMA.

It will be understood that when a polymer or copolymer comprises or is said to contain monomer subunits such as ethoxyethyl methacrylate, this means that the ethoxyethyl methacrylate monomer subunits are reacted and incorporated into the polymer. The monomeric subunits of the claimed compounds may also be in oligomeric form which can be polymerized into specified copolymer compounds.

In some embodiments, the copolymer comprises about 20% to about 40% by weight of the copolymer composition, the second monomer subunit is about 20% to about 40% by weight of the copolymer composition, and the third monomer subunit is about 30% to about 50%, and about >0% to about 5% of a crosslinker.

In some embodiments, the copolymer composition of embodiments of the present invention comprises a copolymer formed from first, second and third monomer subunits, and one or more crosslinking agents, and optionally one or more UV absorbing compounds or monomers, violet and /or consists of or consists essentially of a blue absorber or antioxidant.

In some embodiments, the copolymer comprises TMPTMA and monomer subunits consisting of GMA, bromo-2-hydroxy-3-phenoxypropyl (meth)acrylate and 2-ethoxyethoxyethyl (meth)acrylate, and optionally formed from one or more UV absorbing compounds or monomers, violet and/or blue absorbers or antioxidants.

In some embodiments, the copolymer is

(a) an aliphatic carbon moiety comprising (meth)acrylate groups incorporated in an amount of about 30 to 50 percent, and at least two hydroxyl substituents;

(b) hydroxy and halogen-substituted aryloxyalkyl (meth)acrylates such as bromo-2-hydroxy-3-phenoxypropyl methacrylate incorporated in an amount of about 20 to 40 percent;

(c) an alkoxyalkoxyalkyl (meth)acrylate such as 2-ethoxyethoxyethyl methacrylate incorporated in an amount of about 20 to 40 percent;

(d) a cross-linking agent incorporated in an amount from about >0% to about 5%; and

(e) optionally, one or more optional other ingredients such as water, one or more UV absorbing compounds or monomers, violet and/or blue absorbers and antioxidants

Including, consisting essentially of, or consisting of them.

In some embodiments, the first, second, and third monomer subunits together comprise at least about 70, 75, 80, 85 and/or 90 percent by weight of the monomer subunit composition.

Characteristics of the composition

The copolymer may have a water content of greater than about 15 percent, or greater than about 20 percent, by weight of the copolymer after fully equilibrated in water. In some embodiments, the copolymer has an equilibrium water content in the range of about 15 percent to about 25 percent by weight of the copolymer after fully equilibrating in water. In another embodiment, the water content ranges from about 20 percent to about 30 weight percent of the copolymer after the copolymer is fully in equilibrium with water.

The copolymers possess mechanical and optical properties superior to other materials used to make IOLs, such as increased refractive index relative to the prior art, while also being foldable and possessing high Abbe values. Components of embodiments of the present invention can provide hydrophilic lenses with reduced stickiness, which provide IOLs with desirable and reliable unfolding times while maintaining a high refractive index.

The copolymer has a superior refractive index compared to known hydrophilic lenses, such as Benz IOL25 (see US Pat. No. 6,517,750; a copolymer of 2-hydroxyethyl methacrylate and 2-ethoxyethyl methacrylate). can hold In some embodiments, the refractive index of the copolymers of the disclosure is greater than about 1.47, 1.48, 1.49, or 1.50. These refractive indices can be measured on hydrated or non-hydrated lenses.

Copolymers can be designed to have a wide range of physical properties. In some embodiments, copolymers of the present disclosure may be designed to have a glass transition temperature of at least about 35 °C, for example from about 35 °C to about 100 °C. In a preferred embodiment, the glass transition temperature is about 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, 85°C. °C, will be above 100 °C. Such higher glass transition temperatures can be obtained from non-hydrated copolymers, for example copolymers that are not placed in isotonic saline or water.

Because the copolymers of the present invention are hydrophilic, they may also contain at least about 15 percent, such as 15 percent, 16 percent, 17 percent, 18 percent, 19 percent, 20 percent, 21 percent, 22 percent, 23 percent, 24 percent, It may have an equilibrium water content of 25 percent or more. Copolymers of the present invention can generally be considered hydrophilic due to their high water content. In general, the lenses of the present invention also have similar or higher performance than lenses containing Benz IOL25 (see U.S. Patent No. 6,517,750; a copolymer of 2-hydroxyethyl methacrylate and 2-ethoxyethyl methacrylate). It has an advantageous property over previous lenses because it has a refractive index and is more flexible than other hydrophilic lenses comprising aromatic monomer subunits to increase the refractive index of the resulting polymer, for example because it is more foldable.

In some embodiments, the copolymers of the present invention may have Abbe values greater than 45 or 46. In some embodiments, copolymers of the present invention may have Abbe values of 45, 46, 47, 48 or 49. In some embodiments, copolymers of the present invention may have an Abbe value of 47. The human lens has an Abbe value of about 47. A high Abbe value indicates low chromatic aberration, which is a desirable quality for an IOL. Thus, in certain embodiments, an IOL of the present disclosure has an Abbe value of 45, 46, 47, 48 or 49.

In some embodiments, the Abbe value can be determined by the formula:

Abbe value = (index of refraction at 589 nm - 1) (index of refraction at 486 nm - index of refraction at 656 nm)

In some embodiments, the copolymer contains trace amounts of residual unreacted monomer after polymerization. In some embodiments, polymerization is performed neat (ie, without solvent). In some embodiments, the copolymer is not subjected to a purification step and contains no more than 2 wt%, or no more than 1 wt%, or no more than 0.5 wt% residual unreacted monomer.

lens

Embodiments of the present invention also provide intraocular lenses made at least in part from copolymers of the present invention. Such an intraocular lens includes an optical portion and one or more haptic portions. Typically, the copolymers of the embodiments will make up part or all of the optic of an intraocular lens. In some embodiments, the optical portion of a lens will have a core made from one of the copolymers of the present invention surrounded by a different polymer or material. A lens whose optical portion is at least partially composed of one of the inventive copolymers will typically also have a haptic portion. The haptic portion may also be made of an embodiment copolymer or may be made of a different material, for example another polymer.

In some embodiments, an intraocular lens of the present disclosure has a foldable soft central optic region and an outer peripheral region (haptics-region), wherein both regions are integral lenses made of the same polymer. In other embodiments, the optic and haptic regions may be formed from different types of polymers or materials, if desired. Some lenses may also have haptics composed of different materials, eg one or more haptics are made from the same material as the optics and other haptics are made from materials other than the polymers of this embodiment. Multi-component lenses can be made by embedding one material in another, by co-extrusion methods, by solidifying a hard material around a soft material, or by forming an interpenetrating network of rigid components into a preformed hydrophilic core. If one or more haptic parts are made from a different material than the optic part of the lens, the haptic part can be attached to the optic part in any way known in the art, such as by drilling a hole(s) in the optic part and inserting the haptic part. .

Copolymers of embodiments of the present invention may be designed such that they are foldable so that an intraocular lens may be inserted into an individual eye through a small incision. The haptic portion of the lens tends to provide the required support for the lens in the eye after insertion and unfolding of the lens, and to help stabilize the position of the lens after insertion and closure of the incision. The shape of the haptic portion design is not particularly limited and can be any desired configuration, for example a plate-like or graded thickness spiral filament (also known as a C-loop design).

The optic of the IOL may be approximately 6 mm in diameter prior to hydration. The 6 mm diameter is fairly standard in the art and is generally chosen to cover its fully dilated pupil under naturally occurring conditions. However, other sizes are possible and embodiments of the invention are not limited to intraocular lenses of any particular diameter or size. Furthermore, the lens optics need not be circular; It can also be oval, square, or any other desired shape.

The intraocular lens may further include one or more non-optical haptic components of the IOL extending from the outermost peripheral surface of the optic. The haptic portion component may have any desired shape, for example a graded spiral filament or flat plate cross-section, which is used to support a lens within the posterior chamber of the eye. Lenses can be made with any desired design configuration. If the intraocular lens includes components other than the optical and haptic portions, these other portions may be made of a polymer, such as the haptic and optical portions, or another material, if desired.

The intraocular lens of this embodiment can be inserted into the eye in a known manner. For example, an intraocular lens may be folded prior to insertion into the eye with small, thin forceps of the type typically used by ophthalmologists. After the lens is placed in the target position, it is unfolded and unfolded. As is well known in the art, typically the lens to be replaced is removed prior to intraocular lens insertion. The intraocular lenses of this embodiment can be made from soft, generally physiologically inert, polymeric materials that can provide a clear, transparent, refractive lens body even after folding and unfolding. In some embodiments, the foldable intraocular lenses of the present embodiments can be inserted into any eye by implantation in which the mechanically flexible material is folded and forced through a tube, such as a 1 mm to 3 mm inner diameter tube. In one embodiment, the tube may have an inside diameter of no greater than about 2.0 or 1.9 or 1.8 or 1.7 or 1.6 or 1.5 mm. In one embodiment, the inner diameter is approximately 1.4 to 2.0 mm. In one embodiment, the inner diameter is approximately 1.8 mm, and in another embodiment it is 1.6 mm. In one embodiment, the finished IOL lens is microinjectable, such as a 1.6 Medi-cell injector (eg can be injected through a tube having an internal diameter of approximately 1.6 mm).

Method for preparing the composition

Copolymers of embodiments herein may be prepared using conventional polymerization techniques known to those skilled in the art of polymer chemistry. A crosslinking agent (also referred to as a crosslinking agent) may be used in the polymerization reaction. For example, any suitable crosslinking difunctional, polyfunctional monomer, or combination thereof may be used in an effective amount to obtain the desired crosslinking density. For example, a concentration range of from 0.5 to about 5 (eg, from about 2 to about 3 or from about 2.5 to about 3) weight percent based on the weight of the dry copolymer. Examples of suitable crosslinkers include di-olefinic compounds such as ethylene glycol dimethacrylate (EGDMA), DEGDMA, and tetraethylene glycol dimethacrylate (TEGDMA) and other crosslinkers comprising three or more olefinic polymerizable functionalities; eg trimethylol propane trimethacrylate (TMPTMA). Generally, crosslinkers help enhance the dimensional stability of the resulting polymer.

Initiators may also be used in the polymerization if desired. Any initiator commonly used in the art, such as 2,2-azobis (2,4-dimethylvaleronitrile) and propanenitrile, azo derivatives such as 2-methyl,2,2'-azobis can be used. can The initiator may be a photoinitiator, a thermal initiator, or other type of initiator as will be appreciated by those skilled in the art. In some embodiments, the photoinitiator is CGI 819. The initiator is used in an effective amount for initiation purposes and is generally present at about 0.01 to 1.0 weight percent based on the weight of the polymer.

Copolymers of embodiments of the present invention may also contain additional monomers such as, but not limited to, monomers that impart ultraviolet (UV) absorption to the polymer and/or monomers that impart absorption to the lens, such as blue light blocking. can include UV absorbing monomers are typically aromatic compounds with olefin functional groups. Advantageous UV absorbing compounds may be added prior to polymerization for incorporation into the resulting polymer, as is well known in the art. The UV absorber can preferably be polymerized into the lens matrix to be stable under physiological conditions. Any monomer copolymerizable with the described monomer subunits may optionally be used as long as such monomers do not substantially or adversely affect the basic characteristics of the intraocular lens. Examples of useful additional monomers that can be used are described in U.S. Patent No. 5,326,506, which is incorporated herein by reference, relating to composite intraocular lenses. Additionally, to achieve desired UV absorption properties, see, for example, U.S. Patent No. 6,365,652, or U.S. Pat. Aryl-substituted triazole compounds such as the tris-aryl triazole compounds described in 13/619043 (eg UVX) may be used in low concentrations. These optional additional monomers are preferably present in a total amount of less than 10 weight percent, usually less than 5 weight percent, based on the total weight of the polymer.

In some embodiments, the polymerization reaction is conducted without any solvent.

As described above, it may be useful to add a crosslinking agent such as EGDMA, DEGMA, TEGDMA or TMPTMA, for example, to improve the dimensional stability of the resulting polymer. It may also be advantageous to add UV absorbing compounds and lens monomer subunits prior to polymerization for incorporation into the resulting polymer. The UV absorber should preferably be capable of polymerization into the lens matrix to resist extraction under physiological conditions. The UV-absorbing monomer may be present in an amount effective to obtain the desired UV-absorbing properties, generally less than 4 weight percent of the polymer, such as from 0.01 to about 1 weight percent of the polymer. UV absorbers may be those known in the art, such as natural yellow, benzotriazole, U.S. 13/619043 UV absorbers (eg UVX); and the like.

Examples of specific copolymers useful in embodiments of the present invention are included in Table 1, also discussed in the Examples, wherein all weights used for polymerization assume that all monomer subunits and crosslinkers are incorporated in the copolymer. It is expressed in grams with the percentage of monomer subunits in the polymer shown in parentheses based on the total of all monomer subunits and crosslinker.

In some embodiments, the process does not include a purification step after formation of the polymer due to the low residual unreacted monomer.

formation of the IOL

The intraocular lenses of embodiments of the present invention may be formed by methods known in the art. For example, in an exemplary method, the monomer subunits that form the copolymer can be polymerized into polymer rods, polymer blanks, or disks (formed from the rods), and the blanks are then guided by, for example, turning and milling. cut into lenses The rod may be made by a procedure initiated by polymerization of a mixture of an initiator and a monomer subunit forming an optically transparent soft lens body in a mold, such as a tubular or cylindrical mold. As discussed above, it may be desirable to incorporate cross-linking materials and ultraviolet-absorbing compounds during polymerization or in the resulting polymer matrix. In some embodiments, the polymeric rod is then cut and ground into blanks of the desired diameter and thickness by laid cutting or otherwise machined and machine milled.

Typically, the composite rod is laid cut or ground to a diameter that is 0.5 to 2.0 mm thicker than the desired distance from the center of the lens body to the most distal edge of the leg or haptic portion. This rod is then cut into blanks of uniform thickness. The blank is ground and wrapped into an intraocular lens of an embodiment of the present invention in a conventional manner to a diameter and thickness suitable for blade cutting and mechanical milling.

A general description of the step-by-step method of forming the blank into an intraocular lens is given in the flow diagram below. A person of ordinary skill in the art of intraocular lens manufacturing can, from a review of this specification, use general knowledge in the art of intraocular lens manufacturing and cryogenic machining methods to manufacture intraocular lenses.

An intraocular lens can also be made by molding the copolymer of the present invention to form all or part of the optical portion of the lens. For example, the copolymers of the present invention can be polymerized in a mold with a liquid mixture of monomer subunits and additional components to form an optically clear soft lens body. These shaping methods may include shaping the optic on one-half of the lens, such as the anterior or posterior segment, or shaping the entire lens. If only half of the optic of the lens is formed in the mold, the second side optic can then be machined, as discussed above. In all of these embodiments, additional materials can be molded to allow the machining of various haptic portion designs. The copolymer may optionally be molded as a universal blank in the form of preformed lenses as is known in the art.

application

One application is lenses, including lenses adapted to the human eye, including IOLs.

Additional embodiments are provided in the following non-limiting working examples and contrasted with comparative examples.

working example

GMA refers to glycerol methacrylate or 2,3-dihydroxypropyl methacrylate

Am refers to acrylamide

DMA refers to N,N-dimethylacrylamide

EOEAm refers to 2-ethoxyethyl acrylamide

HEAm refers to hydroxy ethyl acrylamide

HPPMA refers to 2-hydroxy-3-phenoxypropyl methacrylate

Br-HPPMA refers to 4-bromo-2-hydroxy-3-phenoxypropyl methacrylate

EOEOEA refers to ethoxyethoxyethyl acrylate

EOEOEMA refers to ethoxyethoxyethyl methacrylate

EOEMA refers to 2-ethoxyethyl methacrylate

TMPTMA refers to trimethylol propane trimethacrylate

Example 1

Preparation of 4-bromo-2-hydroxy-3-phenoxypropyl methacrylate

Scheme 1.

4-Bromophenol, anhydrous DMF was added to the flask at room temperature under N ₂ . TEAB, and GMA were added along with anhydrous DMF (1L total). The mixture was slowly heated to 70 °C and held at 70 °C for 2 days. Thin layer chromatography (TLC) showed only product with no starting material remaining. The reaction mixture was cooled to room temperature. Water (2 L) was added. Extraction was performed using ethyl acetate (EtOAc) (2 x 1 L). The EtOAc layer was washed with 10% aqueous KOH followed by water, then dried over anhydrous Na ₂ SO ₄ . The organic layer was filtered. Solvent was removed. The residue was purified by column chromatography on silica gel eluting with hexanes (hex) followed by 5% EtOAc/hex. 87 g of a white solid was collected. The white solid was dissolved in CH ₂ Cl ₂ (200 mL). The CH ₂ Cl ₂ solution was washed with 10% KOH aqueous solution followed by water. Solvent was removed. The solid was dissolved in acetone (20 mL). Hexanes (100 mL) was added until the solution became cloudy (add 1 drop of acetone to make the solution clear). The solution was kept at room temperature overnight and a white solid precipitated out. The solution was filtered and dried. A white solid was collected (45 g): mp: 68-69° C.; HPLC: 99.7%; GC: 100%.

Acid content test: Methanol/water (2:1, 200 mL) was neutralized with phenolphthalein in 0.02 N aqueous NaOH solution. 2 g of product was added and dissolved. Aqueous NaOH solution (0.02 N) was added and the red color disappeared within 1 minute.

Example 2

Preparation of 2-hydroxy-3-phenoxypropyl methacrylate

Scheme 2.

Under N ₂ , phenol, anhydrous DMF was added to the flask at room temperature. Anhydrous DMF (1.5 L total) was added along with TEAB, and GMA. The mixture was slowly heated to 70 °C and held at 70 °C for 2 days. TLC showed only product with no starting material remaining. The reaction mixture was cooled to room temperature. Water (2 L) was added. Extraction was performed using EtOAc (3 x 1 L). The EtOAc layer was washed with 10% aqueous KOH followed by water and dried over anhydrous Na ₂ SO ₄ . The organic layer was filtered. Solvent was removed. The residue was purified by column chromatography on silica gel eluting with hex followed by 5% EtOAc/hex. 210 g of a colorless oil were collected. The crude oil was dissolved in CH ₂ Cl ₂ (300 mL). The CH ₂ Cl ₂ solution was washed with 10% KOH aqueous solution followed by water. Solvent was removed. The oil was dissolved in acetone (50 mL). Hexanes (300 mL) was added until the solution became cloudy (add 1 drop of acetone to make the solution clear). The solution was placed in the refrigerator for 2 days and shaken very frequently until a white solid precipitated. The solution was filtered and dried. A white solid was collected (135 g): mp: 28-29° C.; HPLC: 99.6%; GC: 99.1%.

Acid content test: Methanol/water (2:1, 200 mL) was neutralized with phenolphthalein in 0.02 N aqueous NaOH solution. 2 g of product was added and dissolved. Aqueous NaOH solution (0.02 N) was added and the red color disappeared within 1 minute.

Polymer Examples

Unless otherwise stated, the following polymerizations were carried out on a 4-5 g scale.

Example 3

The monomers listed in the table below were combined and mixed. The homogeneous mixture was degassed. The mixture was dispensed into a mold and light-cured at 30° C. for 60 min at 0.25 mW/cm ² followed by 85° C. for 10 min at 3.0 mW/cm ² . The mold was allowed to cool to room temperature. The mold was opened, and the polymer disk was removed and inspected. The polymer exhibited the properties summarized in Table 1.

Table 1

Example 4: Injection Comparison

The 40/30/30 GMA/EOEOEMA/Br-HPPMA compound of Example 3 and the IOL25 were made into similar IOLs. Both materials were injected into a Medicel 1.6 mm Accuject injector. The IOL was loaded by injecting HPMC viscoelastic fluid into the tip and chamber of the injector. All IOLs were loaded in the same way with the leading haptic section facing down. Additional viscoelastic fluid was applied to the top of the part, the injector was closed, and the IOL was injected 3 minutes later. The amount of force required to push the part through the injector was reported on a 0-5 scale. The time taken for the IOL to unfold after implantation was recorded. The room temperature as well as the temperature of the saline into which the IOL was injected were also recorded.

The compound of Example 3 material was injected very gently with minimal force and no damage to the IOL or injector tip was observed. It was also observed that injection of the IOL25 material with the same power IOL required four times the force to pass through the same size injector. Damage to the IOL25 material IOL and the tip of the used injector was also observed.

Table 2

As will be understood by one of ordinary skill in the relevant art, for any and all purposes, particularly in view of providing a written description, all ranges disclosed herein also encompass any and all possible subranges and subranges thereof. covers a combination of Any recited range can be readily recognized as sufficiently delineating and enabling identical ranges to be broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each of the ranges discussed herein can be readily broken down into lower thirds, middle thirds, and upper thirds, and the like. Also, as will be appreciated by those skilled in the art, all language such as "at most", "at least", "greater than", "less than", etc. are inclusive of the recited numbers and subranges as discussed above. refers to the range that can be subsequently decomposed into In the same way, all ratios recited herein also include all lower ratios subsumed within the broader range of ratios.

Those skilled in the art will also note that where the members are grouped together in a general way, such as into a Markush group, the present invention applies not only to the entire group listed, but also to each member of the group individually and It will also be readily appreciated to include all possible subgroups of the main group. Thus, for all purposes, embodiments of the present invention include not only main groups, but also main groups in which one or more of the group members are absent. Embodiments of the present invention also contemplate the explicit exclusion of one or more of the members of any group in the claimed embodiments.

All references, patents and publications disclosed herein are specifically incorporated by reference in their entirety and for all purposes as if fully set forth in their entirety. Unless otherwise specified, “a” or “an” means “one or more”.

While preferred embodiments have been illustrated and described, it should be understood that changes and modifications may be made thereto according to ordinary skill in the art without departing from embodiments in their broader aspects as defined in the following claims. do.

Claims (67)

(a) (i) an aliphatic carbon moiety substituted with a polymerized (meth)acrylate group and two hydroxyl substituents, or
(ii) polymerized (meth)acrylamide substituents
a first monomeric subunit consisting of
(b) polymerized (meth)acrylate groups, and
(i) an aryloxy moiety comprising at least one halogen and
(ii) an aliphatic carbon moiety linking the aryloxy moiety with the polymerized (meth)acrylate group and optionally comprising at least one hydroxyl substituent;
At least one instrument containing
a second monomer subunit different from the first monomer subunit, comprising
(c) polymerized (meth)acrylate groups and
at least one alkoxyalkoxyalkyl side group
a third monomer subunit different from the first and second monomer subunits, comprising
A hydrophilic intraocular lens comprising at least one copolymer comprising
the first monomer subunit is 30% to 50% by weight of the copolymer composition;
the second monomer subunit is from 20% to 40% by weight of the copolymer composition;
The third monomer subunit is 20% to 40% by weight of the copolymer composition.
Hydrophilic intraocular lenses. The method of claim 1, wherein the copolymer,
polymerized (meth)acrylate groups and
at least one alkoxyalkyl side group
a fourth monomer subunit different from the first, second and third monomer subunits comprising
A hydrophilic intraocular lens that further comprises. The copolymer according to claim 1 or 2,
(i) a bridging subunit or
(ii) a cross-linking subunit of a trimethacrylate cross-linking agent
phosphorus monomeric subunit
A hydrophilic intraocular lens that further comprises. 3. A hydrophilic intraocular lens according to claim 1 or 2, wherein the aryloxy group of the second monomer subunit comprises a phenoxy group. 3. The method of claim 1 or 2, wherein the aliphatic carbon moiety of the second monomer subunit is
(i) is substituted with one hydroxyl group, or
(ii) is a C ₃ moiety, or
(iii) represented by -CH ₂ -CHOH-CH ₂ -
Hydrophilic intraocular lenses. 3. A hydrophilic intraocular lens according to claim 1 or 2, wherein the halogen of the second monomer subunit is a bromo moiety. 3. The alkoxyalkoxyalkyl group of claim 1 or 2, wherein the third monomer subunit is
(i) a C ₃ to C ₁₂ group, or
(ii) contains two oxygen atoms, or
(ii) 2-ethoxyethoxyethylin
Hydrophilic intraocular lenses. 3. A hydrophilic intraocular lens according to claim 1 or 2, wherein the aliphatic carbon moiety substituted with two hydroxyl substituents in the first monomer subunit comprises a C ₂ to C ₆ aliphatic carbon moiety. 3. A hydrophilic intraocular lens according to claim 1 or 2, wherein the first monomer subunit is polymerized 2,3-dihydroxypropyl methacrylate. 3. The method of claim 2, wherein the alkoxyalkyl group of the fourth monomer subunit is
(i) a C ₃ to C ₁₂ group, or
(ii) contains a single oxygen atom; or
(iii) 2-ethoxyethylin
Hydrophilic intraocular lenses. According to claim 1 or 2,
the third monomer subunit is polymerized 2-ethoxyethoxyethyl methacrylate;
The second monomer subunit is polymerized

is,
here
R' is methyl.
Y is O;
X is Br;
Z is H;
n is 1;
m is 1;
q is 1, 2, 3, 4, or 5
Hydrophilic intraocular lenses. 3. A hydrophilic intraocular lens according to claim 1 or 2, wherein the copolymer further comprises at least one of a UV absorber, an initiator and/or a crosslinking agent. 3. A hydrophilic intraocular lens according to claim 1 or 2, wherein the copolymer has an equilibrium water content of at least 20% by weight in isotonic saline at 35°C. According to claim 1 or 2,
When placed in saline solution at a temperature of 35°C
(i) has a center thickness of at most 1 mm and unfolds in less than 1 minute; or
(ii) has a center thickness of up to 1 mm and unfolds within 5 to 20 seconds;
Hydrophilic intraocular lenses. According to claim 1 or 2,
(i) has a refractive index of 1.47 to 1.50 at 546 nm and 20° C., or
(ii) a refractive index greater than 1.47 at 546 nm and 20° C.
Hydrophilic intraocular lenses. 3. A hydrophilic intraocular lens according to claim 1 or 2, which can be implanted through a tube having an inner diameter of 1.6 mm. (a) (i) an aliphatic carbon moiety substituted with a (meth)acrylate group and two hydroxyl substituents, or
(ii) a (meth)acrylamide substituent
A first monomer consisting of
(b) (meth)acrylate groups, and
(i) an aryloxy moiety comprising at least one halogen and
(ii) an aliphatic carbon moiety linking the aryloxy moiety with the (meth)acrylate group and comprising at least one hydroxyl substituent;
At least one instrument containing
A second monomer different from the first monomer, comprising
(c) (meth)acrylate groups and
at least one alkoxyalkoxyalkyl side group
A third monomer different from the first and second monomers, comprising
(d) optionally;
(meth)acrylate groups and
at least one alkoxyalkyl side group
A fourth monomer different from the first, second and third monomers comprising
Preparing a comonomer mixture comprising; and
polymerizing the comonomer mixture by adding a photoinitiator or a thermal initiator such as CGI 819 (photoinitiator) and a Vazo type initiator
A method for producing a composition comprising at least one copolymer,
The first monomer is 30% to 50% by weight of the comonomer mixture,
The second monomer is 20% to 40% by weight of the comonomer mixture,
The third monomer is 20% to 40% by weight of the comonomer mixture
Way. 18. The method of claim 17, wherein the initiator is a photoinitiator. 19. The method according to claim 17 or 18, wherein the copolymer after polymerization step
(i) 2% or less by weight; or
(ii) 1% by weight or less;
A method containing residual unreacted monomers of 19. The process according to claim 17 or 18, wherein the comonomer mixture is solvent free. 19. The method of claim 17 or 18, wherein the comonomer mixture is
(i) a crosslinkable monomer, or
(ii) a monomer comprising a crosslinkable trimethacrylate
How to further include. 19. The method of claim 17 or 18, wherein the aryloxy group of the second monomer comprises a phenoxy group. 19. The method of claim 17 or 18, wherein the aliphatic carbon moiety of the second monomer is substituted with one hydroxyl group. 19. The method of claim 17 or 18, wherein the halogen of the second monomer is a bromo moiety. 19. The method of claim 17 or 18, wherein the alkoxyalkoxyalkyl group of the third monomer is 2-ethoxyethoxyethyl. 19. The method of claim 17 or 18, wherein the aliphatic carbon moiety substituted with two hydroxyl substituents in the first monomer comprises a C ₂ to C ₆ aliphatic carbon moiety. 19. The method of claim 17 or 18, wherein the first monomer comprises 2,3-dihydroxypropyl methacrylate. 19. The method of claim 17 or 18, wherein the alkoxyalkyl group of the fourth monomer is 2-ethoxyethyl. The method of claim 17 or 18,
The first monomer comprises 2-ethoxyethoxyethyl methacrylate,
wherein the second monomer comprises bromo-2-hydroxy-3-phenoxypropyl methacrylate
Way. 19. The process according to claim 17 or 18, wherein the comonomer mixture further comprises at least one of a UV absorber, an initiator and/or a crosslinker. delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete